1. Field of the Invention
This invention relates to NMR shift reagents, and in particular, polymer contrast enhancing agents for magnetic resonance imaging, and their use in imaging portions of a patient's body.
2. Brief description of the Prior Art
Magnetic Resonance (hereinafter MR) imaging is one of the newest and least deleterious methods of viewing the interior of the human body. Radio waves interact with protons in a magnetic field to produce images having superior soft-tissue contrast compared to X-ray tomography. However, the technique can be non-specific, that is, it may be impossible to distinguish from between many pathological conditions, such as between cancer and the edema surrounding the cancer, active and inactive multiple sclerosis plaques and bowel from other adjacent organs.
Contrast agents enhance various portions of the MR image by changing, usually decreasing, the relaxation times of the protons in the immediate vicinity to the agent. This allows the area of interest to be much more conspicuous than surrounding tissue. One example of a contrast agent is that disclosed in the European Patent No. 3,302,410 of A.G. Schering for gadolinium diethylene triamine pentaacetic acid complex (hereinafter Gd DTPA). Gd DTPA has been attached to a variety of macromolecules, for example monoclonal antibodies, albumin, lipids and polysaccharides. The structure of DTPA is shown below: ##STR1##
Other agents, such as ethylene diamine tetraacetic acid (hereinafter EDTA), and 1, 4, 7, 10 tetraazacyclododecane, N, N', N", N'"-tetraacetic acid (hereinafter DOTA), have been chelated with Gd in an effort to make a superior contrast agent.
The utility of a specific MRI contrast agent varies depending upon the clinical problem to be addressed and the organ of interest to be imaged. For example, extracellular fluid agents such as gadolinium DTPA, gadolinium DOTA, and gadolinium DTPA BMA (the structure of which is shown further below) work well in organs such as the brain and spinal cord, where the normal brain parenchyma has a barrier to permeability of the contrast agent and pathologic conditions such as cancer do not. However, these contrast agents work poorly for imaging of the vascular system as the majority of the material is lost to the extracellular fluid space. Furthermore, they can at times be deleterious in imaging organs such as the liver and spine in which lesions can be made to appear isointense to normal tissue. They can provoke variable enhancement patterns in organs such as the kidneys in which their high concentration first darkens and then brightens parenchyma. They are poor gut agents because of dilution effects, and poor coating of the bowels.
Some prior art chelates such as gadolinium DOTA and HP-DO3A (the structure of which is shown further below) are cyclic compounds which, although thermodynamically more stable than open chain compounds. However, their synthesis requires a complex, tedious, and expensive process. It would be advantageous for a compound to have improved thermodynamic stability over, say, DTPA or DTPA-BMA, yet not require the expense of ring synthesis.
It would be advantageous in certain conditions (e.g. liver metastasis) for the contrast material to specifically target organ receptors. Examples would be galactose receptors in the lever, polymeric material staying within the blood vessels and heart chambers, or intrathecal administration of a contrast agent with a glucose moiety which might attach to glucose receptors within the brain.
U.S. Pat. No. 4,822,594 to Gibby reports polysaccharide conjugates of Gd DTPA. While these are generally useful compounds, they have an unstable shelf life at neutral pH.
Prior art chelates of Gd, and other paramagnetic metals, suffer from several defects. The body rapidly excretes Gd DTPA, for example. Furthermore, it is not organ specific.
Another problem with known MR enhancing agents is that the proteins that are used to anchor the simple chelates, monoclonal antibodies and the like, may provoke allergic reactions in the recipient. Furthermore, proteins are expensive and carry risks of viral pathogens.
U.S. Pat. No. 4,647,447 to Gries et al. discloses a NMR diagnostic medium containing a well tolerated complex salt formed from the anion of a complexing acid and one or more metal ions. Gries et al. discloses that the complexing acid can be conjugated with biomolecules that are known to concentrate in the organ or part of the organ to be examined. The biomolecules of Gries et al. include insulin, prostaglandins, steroid hormones, amino sugars, peptides, proteins and lipids. Gries et al. includes broad claims to a method of imaging body tissue in a patient by NMR tomography by administering to the patient an effective amount of a pharmaceutical agent comprising an amount, effective to affect such relaxation times, of a paramagnetic, physiologically compatible salt of a physiologically compatible chelate complex of an ion of a lanthanide element of atomic numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or 44 (Claim 24 thereof) and by administering to the patient an effective amount of a pharmaceutical agent comprising an amount, effective to affect such relaxation times, of a paramagnetic, physiologically compatible salt of a complex of an ion and, as a ligand, an acyclic or cyclic complexing agent containing organic nitrogen, phosphorus, oxygen or sulfur, the complexed ion being an ion of a lanthanide element of atomic numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or 44 (Claim 65). However, Gries et al. does not disclose any polyamides of DTPA.
Patent Corporation Treaty Application No. WO 90/03804, to Cacheris, et al. discloses metal chelate compositions of monomeric DTPA-bisamides, of the formula: ##STR2## wherein R.sub.1 to R.sub.3 are each, independently, hydrogen, lower hydroxy (e. g. el. C.sub.1-6) alkyl, hydroxy lower alkyl, or polyhydroxy (C.sub.1-18) alkyl.
U.S. Pat. No. 5,077,037 to Wallace discloses magnetic resonance imaging agents including monomeric, mono or polyhydroxy alkylamides of DTPA.
U.S. Pat. No. 5,087,440 to Cacheris, et al. discloses monomeric DTPA bisamides containing heterocyclic and hydroxyalkyl (C.sub.1-6) amines.
U.S. Pat. No. 5,155,215 to Ranney discloses dextran conjugated Gd-DTPA microspheres, which involve ester linkages.
It would be advantageous to have MR contrast enhancing agents that are organ specific, non-ionic and hydrophilic, do not provoke allergic reactions in the recipient, are not expensive to synthesize, yet are thermodynamically stable and retain better chemical stability.